Using a key protein that governs the release of virulent toxins in bacteria, researchers at the University of California, Davis, School of Medicine and Medical Center have successfully vaccinated and treated mice, preventing infection in up to 90 percent of animals studied. The discovery is reported in the April 17 issue of the journal Science.
The research offers a novel approach to preventing and treating infections caused by Staphylococcus aureus, a bacteria commonly found on skin that can also cause a variety of disorders including blood poisoning, toxic shock syndrome, wound infections, endocarditis, pneumonia and food poisoning. It is one of the most common causes of hospital-acquired infections worldwide, and reports of its growing levels of resistance to last-resort antibiotics such as vancomycin threaten a serious international public health problem if current trends continue.
The new approach works by targeting the pathway that individual bacterial cells use to communicate with each other at the site of infection to simultaneously attack the host. Ultimately, the discovery can be used to develop vaccines and drug therapies to prevent infections in humans and dairy animals as a possible alternative to treatment with antibiotics. The protein may also prove useful as a coating for surgical instruments, catheters and other medical equipment, where the risk of bacterial infection in susceptible patient populations is high.
"Standard antibiotics kill bacteria," says Naomi Balaban, an assistant professor of pathology at the UC Davis School of Medicine and Medical Center and lead author of the study. "Our approach disarms the bacteria by blocking the chain of events that triggers toxin production at the genetic level. Without toxins, S. aureus has no weapons and is rendered harmless."
The production of toxins in S. aureus involves an automatic feedback loop, with a key protein, dubbed RAP (for RNAIII activating protein), acting as a gauge for the growing bacterial colony. RAP is secreted continuously into the surrounding environment by S. aureus cells. However, it is not until a critical concentration is reached that RAP triggers the production of toxins. Differences in levels of RAP may explain why S. aureus, a common, sometimes harmless microbe, becomes more virulent, releasing large quantities of infection-causing toxins.
In the Science article, Dr. Balaban and her colleagues show that 72 percent of mice vaccinated with RAP remained free of skin lesions when exposed to S. aureus. Of the 28 percent of vaccinated mice that developed skin infections, the lesions were 50 percent smaller than in unvaccinated mice. In addition, the researchers found that up to 90 percent of the animals that were pretreated with a small portion of the protein also were protected from infection. This smaller protein is produced by a strain of S. aureus that does not cause disease.
"Our studies show that RAP is a powerful target for preventing infection by S. aureus," says Balaban. "And because our approach leaves the organism alive but unable to cause disease, it may also decrease the likelihood that the organism will develop resistance."
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